Activation of ATP-Sensitive K+ Channels in the Ventromedial Hypothalamus Amplifies Counterregulatory Hormone Responses to Hypoglycemia in Normal and Recurrently Hypoglycemic Rats

Abstract

The mechanism(s) by which glucosensing neurons detect fluctuations in glucose remains largely unknown. In the pancreatic ␤-cell, ATP-sensitive K ؉ channels (K ATP channels) play a key role in glucosensing by providing a link between neuronal metabolism and membrane potential. The present study was designed to determine in vivo whether the pharmacological opening of ventromedial hypothalamic K ATP channels during systemic hypoglycemia would amplify hormonal counterregulatory responses in normal rats and those with defective counterregulation arising from prior recurrent hypoglycemia. Controlled hypoglycemia (ϳ2.8 mmol/l) was induced in vivo using a hyperinsulinemic (20 mU ⅐ kg ؊1 ⅐ min ؊1 ) glucose clamp technique in unrestrained, overnight-fasted, chronically catheterized Sprague-Dawley rats. Immediately before the induction of hypoglycemia, the rats received bilateral ventromedial hypothalamic microinjections of either the potassium channel openers (KCOs) diazoxide and NN414 or their respective controls. In normal rats, both KCOs amplified epinephrine and glucagon counterregulatory responses to hypoglycemia. Moreover, diazoxide also amplified the counterregulatory responses in a rat model of defective hormonal counterregulation. Taken together, our data suggest that the K ATP channel plays a key role in vivo within glucosensing neurons in the ventromedial hypothalamus in the detection of incipient hypoglycemia and the initiation of protective counterregulatory responses. We also conclude that KCOs may offer a future potential therapeutic option for individuals with insulin-treated diabetes who develop defective counterregulation. Diabetes 54:3169 -3174, 2005

Improved motor development and good long-term glycaemic control with sulfonylurea treatment in a patient with the syndrome of intermediate developmental delay, early-onset generalised epilepsy and neonatal diabetes associated with the V59M mutation in the KCNJ11 gene

“…The response to hypoglycaemia may be moderated by the Kir6.2 mutation. K ATP channels are present in the glucose-sensing neurons of the ventromedial hypothalamus that play a key role in the central detection of hypoglycaemia and the initiation of protective counter-regulatory epinephrine (adrenaline) and glucagon responses [14][15][16]. There was undetected hypoglycaemia when on insulin in our patient but formal studies of the hypoglycaemia response in these patients are required.…”

Glucose sensing and the pathogenesis of obesity and type 2 diabetes

“…68 In contrast, the activation of ATPsensitive K þ channels in the VMH amplifies counterregulatory hormone responses to hypoglycemia in normal and recurrently hypoglycemic rats. 69 Although the above studies indicate that Glut2, glucokinase and the K ATP channel are required for central glucose sensing and counter-regulation, it is not yet clear if these different proteins need to be present in the same cells for normal glucose sensing. The K ATP channel has a very broad distribution in the brain and it is unlikely that it has a function in glucose sensing in all the cells in which it is expressed.…”

Bringing Light to the Dark Side of Insulin

“…Reduced VMH K ATP channel activity. To determine whether KCO delivery to the VMH could reverse defective glucose counterregulation, rodents exposed to antecedent hypoglycemia were given bilateral microinjections of either diazoxide or vehicle into the VMH, after which they underwent a hypoglycemic clamp study (41). VMH delivery of diazoxide or a SUR1-specific KCO totally reverses the animal's defective counterregulatory response (Fig.…”

“…K ATP channel activity. To evaluate whether K ATP channel activity of VMH neurons alters glucose counterregulation, K ATP channel openers (KCOs) (activators), K ATP channel closers (blockers), or vehicle (control) were bilaterally microinjected directly into the VMH of awake, chronically catheterized nondiabetic rats before a hypoglycemic clamp study (41,42). VMH microinjection of diazoxide, a KCO, reduced by 50% the glucose infusion rate needed to maintain hypoglycemia and increased the response of both epinephrine and glucagon to hypoglycemia threefold (P Ͻ 0.05).…”